A great deal of evidence supports the view that people continue to smoke tobacco products, despite the widely publicized health risks associated with smoking, because of the reinforcing effects of nicotine. Substantial research literature suggests that nicotine contributes to and interacts with cigarette smoking behavior. It appears to be primarily the central actions of nicotine that tobacco smokers seek, and animal studies confirm the importance of central nicotinic actions in controlling behavior (see, e.g., Henningfield & Goldberg (1985) in Behavioral Pharmacology, Seiden & Blaster (eds), Alan R. Liss, N.Y., pp 443-449; Stolerman (1986) in Handbook of Psychopharmacology, Vol. 19, Iversen, Iversen, & Snyder (eds.), Plenum, N.Y.). Nicotine blockade therapy represents an alternative pharmacotherapeutic approach to tobacco use and cigarette smoking cessation (see, Stolerman, I. P. (1986) Br. J. Addiction 81:47-53; Clarke, P. B. S. (1993) Biochem Soc. Symp. 59:83-95). Nicotine blockade therapy is radically different from other approaches, since it should permit "pharmacological extinction" of smoking behavior. Smokers attempting to quit by this method would be administered a centrally-active nicotinic receptor antagonist while continuing to smoke. With every puff, the association between smoking and delivery of nicotine-associated reinforcement would be unlearned. This should reduce long-term craving and hence provide much lower relapse rates than other approaches.
Mecamylamine is a nicotinic antagonist, penetrates the blood-brain barrier, and blocks nicotinic effects both in the brain and periphery (see, Martin, B. R. et al. (1993) Med. Chem. Res. 2:564-577). Mecamylamine until recently was marketed as a hypotensive drug, Inversine.RTM. (Merck & Co.) to be administered in an oral dosage form. Preliminary studies of chronic mecamylamine administration as a potential aid to smoking cessation show that mecamylamine blocks the effect of nicotine and significantly reduces nicotine withdrawal symptoms, i.e., craving for cigarettes. The disadvantages of orally administered mecamylamine are those associated with its peripheral effects, resulting from its blockade of autonomic ganglia. These side effects, first noted when mecamylamine was used in the treatment of hypertension, include postural hypotension, orthostatic dizziness, nausea, vomiting, constipation, urinary retention, dryness of the mouth, abdominal cramps, decreased libido, impotence, blurred vision, fatigue and weakness. A major difficulty with prior attempts to use mecamylamine in smoking cessation programs has been persuading cigarette smokers to accept these unpleasant effects and at the same time give up the positively reinforcing effects of nicotine.
Chlorisondamine, a representative of quaternary ammonium compounds, is a bisquaternary noncompetitive ganglion-blocking drug which has been used clinically as an antihypertensive. Chlorisondamine does not readily cross the blood-brain barrier and does not block the behavioral effects of nicotine when administered systemically, although it blocks its peripheral effects (see, e.g., El-Bizri, H., & Clarke, P. B. S. (1994) Br. J. Pharmacol 111:414-418). Published reports indicate that injection of small doses of chlorisondamine directly into the brain block the behavioral effects of nicotine and a single brain injection completely blocked the effects of nicotine for several weeks (Clarke, P. B. S. & Kumar, R. (1983) Br. J. Pharmacol. 80:587-594). It has also been reported that a persistent central nicotinic blockade can also be achieved by giving the drug systemically in high doses in rats (Clarke, P. B. S. (1984) Br. J. Pharmacol. 83:527-535). As with mecamylamine, high doses of a ganglionic blocker such as chlorisondamine will produce serious and unpleasant side effects and it is not known whether systemic administration of centrally-active high doses would be safe in humans.
Therefore, in view of the aforementioned deficiencies attendant with prior art methods of nicotinic antagonists administration, it should be apparent that there still exists a need in the art for a safe and convenient method of administering nicotinic antagonists to patients at safe and effective doses.